beta-alkylcholine salts and their acyl esters



Patented Apr. 30, 1940 1 UNITED STATES PATENT OFFICE fi-ALKYLCHOLINESALTS AND THEIR ACYL ESTERS Jersey No Drawing. Original applicationDecember 4,

1935, Serial No. 52,872. Divided and this applieation November 1, 1937,Serial No. 172,239

6 Claims.

This application is a division of our co-pending application, Serial No.52,872, filed December 4, 1935, which issued as Patent No. 2,135,521 onNovember 8, 1938.

This invention relates to higher homologues of beta-methylcholine halideand their acyl derivatives, and to processes for their production.

The co-pending application of one of us, Randolph T. Major, inassociation with Joseph K. Cline, Serial No. 733,604, filed July 13,1934, which issued as Patent No. 2,040,146 on May 12, 1936, relates tothe preparation of acetyl-betamethylcholine chloride. We have nowsucceeded in producing, as well, its hitherto unknown higher homologues.

The general series of the beta-n-alkyl choline halides which are thesubject of the present invention have been tested pharmacologically withinteresting results. It has been found that, while the acyl derivativesof these new compounds exhibit generally a muscarine action similar tothat of acetyl-beta-methylcholine chloride, the nonacylated higherhomologues exhibit rather unexpected and important differences in theirtherapeutic action. Thus, for instance, while the beta-hexylcholine andthe beta-heptylcholine chlorides exhibit a muscarine action, thebetapropylcholine and the beta-butylcholine chlorides exhibit thetypical, so-called nicotinic action which is a matter of considerablepractical therapeutic interest.

Broadly, the process of the present invention is directed to theproduction of beta-alkylcholine halides by the condensation of givenchlorhydrins with methyl amines.

One preferred modification of our process for producing thesebeta-alkylcholine salts consists in reacting upon an appropriatechlorhydrin with dimethylamine and converting the resultingdimethylamino-alkanol into its methiodide, from which thebeta-n-alkylcholine chloride may be readily obtained, and which lattermay then be readily acylated by appropriate means. The process outlinedabove is preferably directed to the production of the higher of thehomologues of beta-methylcholines which constitute the subject-matter ofour invention, but some of the relatively lower homologues in question,as for instance, beta-ethylcholine chloride, beta-npropylcholinechloride, etc. may be prepared directly by treating the appropriatelyselected chlorhydrin With trimethylamine, thus avoiding the intermediatestep of forming the methiodide.

While either modification of the above described method may be employed,ior the preparation of all of the homologues herein contemplated, it hasbeen found more convenient, because of the rapid increase inhygroscopicity with increase in size of the alkyl group, to prepare thehigher homologues by means of the reaction of methyl iodide ondimethylaminoalkanol, so that the necessary purification may be morereadily effected.

The appropriate chlorhydrins used as starting materials in each instancewere prepared by the reaction of chloracetaldehyde with the selectedGrignard reagent. The hitherto unreported l-chorononanol-Z, was alsoprepared in this Way.

During the working out of our process a number of intermediate compoundswere prepared which had not previously been described; these include1-dimethylamino-butanol-2, l-dimethylamino-pentanol-2,1-dimethylamino-hexanol-Z, l-dimethylamino-octanol-2, andl-dimethylamino-nonanol-2.

The following description of the more detailed steps of the processexemplifies specific adaptations of the general method set forth aboveto the ultimate production of various specific acetylbeta-alkylcholinehalides, which are embraced within the scope of our invention.

Preparation of 1-dimethylamino-alkanoZ-2.- The appropriate chlorohydrinis heated with a solution of two mols. of dimethylamine in benzene at115-120 C. for about hours, and isolated from the resulting mixture bythe usual methods. The compounds obtained are mobile, colorless liquidspossessing a strong amine-like odor. 1-dimethylamino-butanol-2 and'l-dimethylaminopentanol-2 are very soluble in Water, but the higherhomologues are insoluble in water. All of the compounds are soluble inthe usual organic solvents.

Preparation of beta-n-alkylcholine iodide.- The methiodides of theL-dimethylamino-alkano1-2 compounds are prepared by treating the latterwith methyl iodide at room temperature. They are recrystallized fromwarm acetone to which other is added, and occur in the form ofnon-hygroscopic white, micro-crystalline solids.

Preparation of beta-n-alkylcholine chloride. The beta-n-alkylcholineiodides are converted to their corresponding chlorides by reacting uponthem with AgCl in alcoholic solution by the methods of Jones and Major(Jour. Am. Chem. So., 52, 309 1930). The silver salts formed in thereaction are removed by filtration, and the beta-n-alkylcholine chlorideis precipitated by the addition of anhydrous ether to the filtrate.

The last traces of silver chloride are removed by adding the precipitateto a saturated solution methylamino-a l k a n o l s beta-n-alkylcholineiodides, chlorides, and acetyl derivatives, shown on of hydrogen sulfidein absolute alcohol. Actithe same line in the other columns of thetable.

Ohlorohydrins Alkyl R (CHa)zN-OH:GHOHR (OHahNIOIEhOHOHRl-chlorobutanol-Z O1H B. P. 142-144 C. 760/mm M. P. l623 C.1-chloropentanol-2 'n-Ci B. P. M P l98200 C l-chlorohexanol-Z. n-C Ho B.P. P -92" C l-chloroheptanol-Z 1143 11 B. P. P. 98100 C1-chloro-octanol-2 [l-C5H13. B.,P P. 109-1l0 C. 1-chlorononanol-2 n-O HB. P P. l22.5123.5 O.

Ghlorohydrins Alkyl R (CH3)3NC1GH2OHOHR (CHa)aNC1CHgC/H(OOCOH )R1-chl0robutan0l2 0 11 M. P. 174-45 0 M. P 144-6" 0 l-chloropentanol-2n-C H M. P. ll5-7 C... M. P 1689 C l-chlorohexanol-Z. 1143 11 M. P.l00.5-l02 O M. P l867 C l-chloroheptanol-Z. n-C H M. P. 7274 C M. P182-4 G l-chloro-octanol 2 .l. n-CcHn. M. P. 6971 0.... .l M. P 1697l C1-chloron0nan01-2 11-G7H15- M. P. 9799 C M. P 176-7 C vated charcoal isadded and the mixture filtered.

Beta-ethylcholine chloride may be recrystallized from butyl alcohol,beta-propylcholine chloride may be recrystallizedfrom' a mixture ofbutyl alcohol and isopropyl ether, and beta-butylcholine chloride may berecrystallized with 'difiiculty from a mixture of butyl alcohol andbenzene. The remaining compounds are obtained in the form of gums whichcrystallize on standing in a desiccator. The final products are obtainedin the form of white, extremely hygroscopic solids.

Preparation of acetyl-beta-n-allcylcholine chl0-ride.Acetyl-beta-n-alkylcholine chloride is prepared according to themethod described by Major and Cline in their aforementioned .copendingapplication, Ser. No; 733,604. In accordance-with that method, a mixtureof ,beta n-alkylcholine chloride with an excess of acetic anhydride isseated for six hours at C. Dry ether is then added to the cooledsolution. The precipitate which forms is Washed several times with etherand then dissolved in absolute alcohol, and then the acetylated compoundreprecipitated by the addition of dry ether. The products are obtainedin the form of white, crystalline hygroscopic solids.

Examples for the. production of other products of this series can bereadily derivedby reference to the table given below, with the selectionof the appropriate chlorhydrin. Thus, the selection of any givenchlorhydrin shown in the first column of the table, and its treatmentinvolving produce, respectively, the corresponding di- According to theother modification of our process, as mentioned above, for thepreparation of the beta-ethyl, beta-propyl and beta-butylcholinechlorides, trimethylarnine is condensed with the appropriate chlorhydrinin. benzene solution at C. for about 24 hours. The resulting cholinechlorides are precipitated by the addition of ether and recrystallizedfrom organic solvents as indicated.

We claim as our invention:

1. Acetyl derivatives of beta-alktvlcholine halide wherein the alkylradicals contain from two to seven carbon atoms, inclusive.

2. Acetyl beta-ethylcholine chloride.

3. Acetyl beta-n-butylcholine chloride.

4. Acetyl betan-heptylch0line chloride. I

5. Process for the production of acetylbetaalkylcholine halides, whereinthe alkyl radicals contain from two to seven carbon atoms, inclusive,which comprises reacting upon the corresponding chlorhydrin withdimethylamine to obtain the corresponding amino-alkanol, converting theamino-alkanol to its methiodide, reacting upon the iodide with silverchloride to obtain the corresponding choline chloride and acetylating'the latter.

6. Process for the production ofacetyl beta,- alkylcholine chlorideswherein the alkyl radicals contain from two to'four carbon atoms,inclusive, which comprises condensing th selected chlorhydrin withtrimethylamine and acetylating the resulting beta-alkylcholine chloride.

RANDO'LPH T. MAJOR. HOWARD T. BONNETT.

